Potential folding-function interrelationship in proteins

Adi Barzilai, Sandeep Kumar, Haim Wolfson, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The possibility is addressed that protein folding and function may be related via regions that are critical for both folding and function. This approach is based on the building blocks folding model that describes protein folding as binding events of conformationally fluctuating building blocks. Within these, we identify building block fragments that are critical for achieving the native fold. A library of such critical building blocks (CBBs) is constructed. Then, it is asked whether the functionally important residues fall in these CBB fragments. We find that for over two-thirds of the proteins in our library with available functional information, the catalytic or binding site residues lie within the CBB regions. From the evolutionary standpoint, a folding-function relationship is advantageous, since the need to guard against mutations is limited to one region. Furthermore, conformationally similar CBBs are found in globally unrelated proteins with different functions. Hence, substituting CBBs may lead to designed proteins with altered functions. We further find that the CBBs in our library are conformationally unstable.

Original languageEnglish
Pages (from-to)635-649
Number of pages15
JournalProteins: Structure, Function and Genetics
Issue number4
StatePublished - 1 Sep 2004


FundersFunder number
National Cancer InstituteZ01BC010440


    • Folding and function
    • Protein building block
    • Protein design
    • Protein folding
    • Protein function
    • Structure and function


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